The present invention pertains to biodegradable polymers comprising a lactone, biodegradable compositions comprising the polymer and a therapeutic agent, the use of the compositions for the sustained release of therapeutic agents, wherein the therapeutic agent is reversibly immobilized on the polymer matrix using ionic complexation between the latent carboxylic groups present on the lactone bearing polymer matrix and the cationic group on the therapeutic agent.
In order to overcome the multiple dosing regime associated with therapy involving therapeutic agents, which includes peptides and proteins, having a short in vivo half life, numerous technologies are being evaluated for the sustained release of these therapeutic agents. One of these technologies is the encapsulation of drugs in biodegradable matrices such as polyesters, polycarbonates, polyanhydrides, polyorthoesters, polyphosphazenes, polyphosphoesters and the like (see U.S. Pat. No. 4,675,189; U.S. Pat. No. 4,767,628; U.S. Pat. No. 5,271,945; WO 93/20126; GB Patent No. 2,145,422). The biodegradable microparticles containing the therapeutic agent(s) slowly release to maintain an effective plasma level for several days or even for months. The release of the therapeutic agent is dictated by a variety of factors arising from the polymer matrix as well as the physical characteristics of the therapeutic agent, making it possible to engineer the release profile by properly selecting the parameters governing them. The biodegradable polymer matrix degrades in vivo to non-toxic metabolites, at rates depending on the chemical nature of the polymer.
However, one of the many problems, encountered during the encapsulation of therapeutic agents in such biodegradable matrices is the inherent incompatibility between the polymer matrix and the therapeutic agent, such as a polypeptide. This incompatibility often leads to poor encapsulation efficiency as manifested during the emulsion solvent evaporation process, described by the oil-in-water process (P. B. O'Donnell and J. W. McGinity in Advanced Drug Delivery Reviews, 28(1997), 25–42.). Another consequence of the incompatibility between the polymer matrix and a therapeutic agent, is the formation of phase separated domains inside the microparticle. The release of a therapeutic agent from such a phase separated, non-homogenous system becomes non-predictable. One of the ways to overcome such incompatibility is to anchor the therapeutic agent onto a polymer matrix using reversible bonds such as ionic bonds. These ionic complexes are formed between carboxylic functionalities of the polyester and cationic groups of the therapeutic agent as described in the U.S. Pat. No. 5,672,659. The carboxylic acid functionalized polyesters were obtained by the ring opening polymerization of lactones using hydroxycarboxylic acid as an ‘initiator’, whereby the molecular weight of the resulting polyester is controlled by the molar ratio of the hydroxycarboxylic acid with respect to the monomers. The hydroxy group present in the hydroxycarboxylic acid is expected to participate in the ring opening polymerization, producing telechelic polymers having hydroxy and carboxylic groups at the chain extremities. However, the presence of carboxylic group in the initiator can interfere with the polymerization, as discussed by Zhang et al, in Journal Polymer Science, Polymer Chemistry Ed. 1994, 32,2965.
In this context the teachings of the present invention become relevant. Five membered ring lactones and certain six membered lactones (see review by Johns, D. H. et al., in Ring Opening Polymerization, edited by K. J. Ivin and T. Saegusa, Elsevier Applied Science Publishers, N.Y.) are thermodynamically stable and are considered non-polymerizable under the normal conditions of polymerization described by the present invention. An active hydrogen present on a five membered ring lactone, can be used to initiate the polymerization of other lactones, without affecting the five membered ring lactone. Therefore the five membered ring lactones can be incorporated intact, without unfavorably affecting the polymerization as would have been the case when hydroxy carboxylic acids are used as the initiator. These five membered ring lactones can be selectively used to anchor a therapeutic agent such as a polypeptide either by ionic complexation or by covalent conjugation.
Hashimoto et al., describe the synthesis of polyurethanes containing glucarodilactones and mannarodilactones by the reaction between the dihydroxy groups present on the dilactone with diisocyanates (Journal of Polymer Science: Part A, Polymer Chemistry 1995, 33, 1495). However, such monomers have never been used in the synthesis of polyesters, polyorthoesters, polyphosphazenes, polycarbonates, polyanhydrides, polyphosphoesters, and the like.